Composition and process

ABSTRACT

The present invention relates to novel compositions of matter and novel processes for preparing these compositions of matter. Moreover, there are provided novel methods by which certain of these novel compositions of matter are employed for pharmacologically useful purposes.

DESCRIPTION

1. Background of the Invention

The present invention relates to novel compositions of matter and novel processes for preparing these compositions of matter. Moreover, there are provided novel methods by which certain of these novel compositions of matter are employed for pharmacologically useful purposes.

The present invention is specifically concerned with novel analogs of prostacyclin or PGI₂. Specifically, the present invention is concerned with ring-modified analogs of carbacyclin or 6a-carba-prostacyclin.

Prostacyclin is an endogenously produced compound in mammalian species, being structurally and biosynthetically related to the prostaglandins (PG's). In particular, prostacyclin exhibits the structure and carbon atom numbering of formula I. For convenience, prostacyclin is often referred to simply as "PGI₂ ". Carbacyclin, 6a-carba-PGI₂, exhibits the structure and carbon atom numbering indicated in formula II. Likewise, for convenience, carbacyclin is referred to simply as "CBA₂ ".

As is apparent from inspection of formulas I and II, prostacyclin and carbacyclin may be trivially named as derivatives of PGF-type compounds, e.g., PGF₂ α of formula III. Accordingly, prostacyclin is trivially named 9-deoxy-6,9α-epoxy-(5Z)-5,6-didehydro-PGF₁ and carbacyclin is named 9-deoxy-6,9α methano-(5E)-5,6-didehydro-PGF₁. For description of prostacyclin and its structural identification, see Johnson, et. al., Prostaglandins 12:915 (1976).

For convenience, the novel prostacyclin or carbacyclin analogs describing them will be referred to by the trivial, art-recognized system of nomenclature described by N. A. Nelson, J. Med. Chem. 17:911 (1974) for prostacyclins. Accordingly, all of the novel prostacyclin derivatives herein will be named as 9-deoxy-PGF₁ -type compounds, PGI₂ derivatives, or preferably as CBA₂ derivatives.

In the formulas herein, broken line attachments to a ring indicate substituents in the "alpha" (α) configuration, i.e., below the plane of said ring. Heavy solid line attachments to a ring indicate substituents in the "beta" (β) configuration, i.e., above the plane of said ring. The use of wavy lines (˜) herein will represent attachment of substituents in the alpha or beta configuration or attached in a mixture of alpha and beta configurations. Alternatively wavy lines will represent either an E or Z geometric isomeric configuration or the mixture thereof.

A side chain hydroxy at C-15 in the formulas herein is in the S or R configuration as determined by the Cahn-Ingold-Prelog sequence rules, J. Chem. Ed. 41:16 (1964). See also Nature 212:38 (1966) for discussion of the stereochemistry of the prostaglandins which discussion applies to the novel prostacyclin or carbacyclin analogs herein. Molecules of prostacyclin and carbacyclin each have several centers of asymmetry and therefore can exist in optically inactive form or in either of two enantiomeric (optically active) forms, i.e., the dextrorotatory and laveorotatory forms. As drawn, the formula for PGI₂ corresponds to that endogenously produced in the mammalian species. In particular, refer to the stereochemical configuration at C-8 (α), C-9 (α), C-11 (α) and C-12 (β) of endogenously produced prostacyclin. The mirror image of the above formula for prostacyclin represents the other enantiomer. The racemic form of prostacyclin contains equal numbers of both enantiomeric molecules.

For convenience, reference to prostacyclin and carbacyclin will refer to the optically active form thereof. Thus, with reference to prostacyclin, reference is made to the form thereof with the same absolute configuration as that obtained from the mammalian species.

The term "prostacyclin-type" product, as used herein, refers to any cyclopentane derivative herein which is useful for at least one of the same pharmacological purposes for which prostacyclin is employed. A formula as drawn herein which depicts a prostacyclin-type product or an intermediate useful in the preparation thereof, represents that particular stereoisomer of the prostacyclin-type product which is of the same relative stereochemical configuration as prostacyclin obtained from mammalian tissues or the particular stereoisomer of the intermediate which is useful in preparing the above stereoisomer of the prostacyclin type product.

The term "prostacyclin analog" or "carbacyclin analog" represents that stereoisomer of a prostacyclin-type product which is of the same relative stereochemical configuration as prostacyclin obtained from mammalian tissues or a mixture comprising stereoisomer and the enantiomers thereof. In particular, where a formula is used to depict a prostacyclin type product herein, the term "prostacyclin analog" or "carbacyclin analog" refers to the compound of that formula or a mixture comprising that compound and the enantiomer thereof.

2. Prior Art

Carbacyclin and closely related compounds are known in the art. See Japanese published applications 4,063,059 and 4,063,060, also abstracted respectively as Derwent Farmdoc CPI Nos. 481548/26 and 48155/26. See also British published specification 2,021,265 and German Offenlungsschrift No. 2,900,352, abstracted as Derwent Farmdoc CPI No. 54825B/30. See also British published application Nos. 2,017,699, 2,014,143 and 2,013,661.

The synthesis of carbacyclin and related compounds is also reported in the chemical literature, as follows: Morton, D. R., et al., J. Organic Chemistry, 44:2880 (1979); Shibasaki, M., et al. Tetrahedron Letters, 433-436 (1979); Kojima, K., et al., Tetrahedron Letters, 3743-3746 (1978); Nicolaou, K. C., et al., J. Chem. Soc., Chemical Communications, 1067-1068 (1978); Sugie, A., et al., Tetrahedron Letters 2607-2610 (1979); and Shibasaki, M., Chemistry Letters, 1299-1300 (1979), and Hayashi, M., Chem. Lett. 1437-40 (1979).

SUMMARY OF THE INVENTION

The present specification particularly provides:

(a) a carbacyclin intermediate of formula IV, V, or VI; and

(b) a carbacyclin analog of formula VII;

wherein n is the integer 1 or 2;

wherein R₁₈ is hydrogen, hydroxy, hydroxymethyl, --OR₁₀ or --CH₂ OR₁₀, wherein R₁₀ is an acid-hydrolyzable protective group;

wherein Y₁ is trans--CH═CH--, cis--CH═CH--, --CH₂ CH₂ --, or --C.tbd.C--;

wherein M₆ is α-OR₁₀ :β-R₅ or α-R₅ :β-R₁₀, wherein R₅ is hydrogen or methyl and R₁₀ is an acid hydrolyzable protective group;

wherein R₃₂ is hydrogen or R₃₁, wherein R₃₁ is a hydroxyl hydrogen replacing group;

wherein L₁ is α-R₃ :β-R₄, α-R₄ :β-R₃, or a mixture of α-R₃ :β-R₄ and α-R₄ :β-R₃, wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro;

wherein Z₁ is

(1) --(CH₂)_(g) --C(R₂)₂, wherein g is 0, 1, 2, or 3 and R₂ is hydrogen or fluoro, or

(2) trans--CH═CH--;

wherein R₇ is

(1) --(CH₂)_(m) --CH₃, wherein m is an integer from one to 5, inclusive;

(2) phenoxy;

(3) phenoxy substituted by one, two or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituent are other than alkyl;

(4) phenyl;

(5) phenyl substituted by one, two or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl;

(6) benzyl, phenylethyl, or phenylpropyl; or

(7) benzyl, phenylethyl, or phenylpropyl substituted by one, two or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl;

(8) cis-CH═CH--CH₂ --CH₃ ; or

(9) --(CH₂)₂ --CH(OH)--CH₃ ;

with the proviso that R₇ is phenoxy or substituted phenoxy, only when R₃ and R₄ are hydrogen or methyl, being the same or different;

wherein R₃₁ is a hydroxyl hydrogen replacing group;

wherein R₈ is hydroxy, hydroxymethyl, or hydrogen;

wherein M₁ is α-OH:β-R₅ or α-R₅ :β-OH, wherein R₅ is hydrogen or methyl;

wherein X₁ is

(1) --COOR₁, wherein R₁ is

(a) hydrogen;

(b) alkyl of one to 12 carbon atoms, inclusive;

(c) cycloalkyl of 3 to 10 carbon atoms, inclusive;

(d) aralkyl of 7 to 12 carbon atoms, inclusive;

(e) phenyl;

(f) phenyl substituted with one, 2 or 3 chloro or alkyl of one to 3 carbon atoms;

(g) phenyl substituted in the para position by

(i) --NH--CO--R₂₅,

(ii) --CO--R₂₆,

(iii) --O--CO--R₂₇, or

(iv) --CH═N--NH--CO--NH₂ wherein R₂₅ is methyl, phenyl, acetamidophenyl, benzamidophenyl, or --NH₂ ; R₂₆ is methyl, phenyl, --NH₂, or methoxy; and R₂₇ is phenyl or acetamidophenyl; inclusive, or

(h) a pharmacologically acceptable cation;

(2) --CH₂ OH;

(3) --COL₄, wherein L₄ is

(a) amino of the formula --NR₂₁ R₂₂, wherein R₂₁ and R₂₂ are

(i) hydrogen;

(ii) alkyl of one to 12 carbon atoms, inclusive;

(iii) cycloalkyl of 3 to 10 carbon atoms, inclusive;

(iv) aralkyl of 7 to 12 carbon atoms, inclusive;

(v) phenyl;

(vi) phenyl substituted with one, 2 or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro;

(vii) carboxyalkyl of 2 to 5 carbon atoms, inclusive;

(viii) carbamoylalkyl of 2 to 5 carbon atoms, inclusive;

(ix) cyanoalkyl of 2 to 5 carbon atoms, inclusive;

(x) acetylalkyl of 3 to 6 carbon atoms, inclusive;

(xi) benzoylalkyl of 7 to 11 carbon atoms, inclusive;

(xii) benzoylalkyl substituted by one, 2 or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, alkoxy of one to 3 carbon atoms, inclusive, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro;

(xiii) pyridyl;

(xiv) pyridyl substituted by one, 2 or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive;

(xv) pyridylalkyl of 6 to 9 carbon atoms, inclusive;

(xvi) pyridylalkyl substituted by one, 2 or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy or alkyl of one to 3 carboxy atoms, inclusive;

(xvii) hydroxyalkyl of one to 4 carbon atoms, inclusive;

(xviii) dihydroxyalkyl of one to 4 carbon atoms, or

(xix) trihydroxyalkyl of one to 4 carbon atoms; with the further proviso that not more than one of R₂₁ is other than hydrogen or alkyl;

(b) cycloamino selected from the group consisting of

(i) pyrrolidino,

(ii) piperidino,

(iii) morpholino,

(iv) piperazine,

(v) hexamethyleneimino

(vi) pyrrolino,

(vii) 3,4-didehydropiperidinyl, or

(viii) pyrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino, or 3,4-didehydropiperidinyl substituted by one or 2 alkyl of one to 12 carbon atoms, inclusive;

(c) carbonylamino of the formula --NR₂₃ COR₂₁, wherein R₂₃ is hydrogen or alkyl of one to 4 carbon atoms and R₂₁ is other than hydrogen, but otherwise as defined above;

(d) sulfonylamino of the formula --NR₂₃ SO₂ R₂₁, wherein R₂₁ and R₂₃ are as defined in (c);

(4) --CH₂ NL₂ L₃, wherein L₂ and L₃ are hydrogen or alkyl of one to 4 carbon atoms, inclusive, being the same or different, or the pharmacologically acceptable acid addition salts thereof when X₁ is --CH₂ NL₂ L₃.

With regard to the divalent substituents described above (e.g., L₁ and M₁), these divalent radicals are defined as α-R_(i) :β-R_(j), wherein R_(i) represents the substituent of the divalent moiety in the alpha configuration with respect to the ring and R_(j) represents the substituent of the divalent moiety in the beta configuration with respect to the plane of the ring. Accordingly, when M₁ is defined as α-OH:β-R₅, the hydroxy of the M₁ moiety is in the alpha configuration, i.e., as in PGI₂ above, and the R₅ substituent is in the beta configuration.

The novel prostacyclin analogs herein, (i.e., formula VII compounds) are all named as CBA₂ compounds by virtue of the substitution of methylene for oxa in the heterocyclic ring of prostacyclin. The formula VII compounds where n is 2 are further characterized as 7a-homo-CBA₂ compounds by virtue of the cyclohexyl ring replacing the heterocyclic ring of prostacyclin. Further, the formula VII compounds are all named as 6a,9-didehydro-CBA₂ compounds by virtue of the cyclopentene ring replacing the heterocyclic ring of prostacyclin.

When R₅ is methyl, the prostacyclin analogs are all named as "15-methyl-CBA" compounds. Further, except for compounds wherein Y₁ is cis-CH═CH--, compounds wherein the M₁ moiety contains an hydroxyl in the beta configuration are additionally named as "15-epi-CBA" compounds.

For the compounds wherein Y₁ is cis-CH═CH--, then compounds wherein the M₁ moiety contains an hydroxyl in the alpha configuration are named as "15-epi-CBA" compounds. For a description of this convention of nomenclature for identifying C-15 epimers, see U.S. Pat. No. 4,016,184, issued Apr. 5, 1977, particularly columns 24-27 thereof.

Those CBA analogs wherein Z₁ is --(CH₂)_(g) --CF₂ -- are characterized as "2,2-difluoro-CBA" type compounds. For those compounds wherein g is zero, 2 or 3, the prostacyclin analogs so described are further characterized as 2-nor, 2a-homo, or 2a,2b-dihomo, since in this event the X₁ -terminated side chain contains 4, 6, or 7 carbon atoms, respectively, in place of the five carbon atoms contained in PGI₂. The missing carbon atom is considered to be at the C-2 position such that the C-1 carbon atom is connected to the C-3 position. The additional carbon atom or atoms are considered as though they were inserted between the C-2 and C-3 positions. Accordingly, these additional carbon atoms are referred to as C-2a and C-2b, counting from the C-2 to the C-3 position.

The novel prostaglandin analogs herein which contain --(CH₂)₂ --, cis-CH═CH--, or --C.tbd.C-- as the Y₁ moiety, are accordingly referred to as "13,14-dihydro," "cis-13," or "13,14-didehydro" compounds, respectively.

When R₇ is --(CH₂)_(m) --CH₃, wherein m is as defined above, the compounds so described are named as "19,20-dinor," "20-nor," "20-methyl" or "20-ethyl" compounds when m is one, 2, 4 or 5, respectively.

When R₇ is phenyl and neither R₃ nor R₄ is methyl, the compounds so described are named as "16-phenyl-17,18,19,20-tetranor" compounds. When R₇ is substituted phenyl, the corresponding compounds are named as "16-(substituted phenyl)-17,18,19,20-tetranor" compounds. When one and only one of R₃ and R₄ is methyl or both R₃ and R₄ are methyl, then the corresponding compounds wherein R₇ is as defined in this paragraph are named as "16-phenyl or 16-(substituted phenyl)-18,19,20-trinor" compounds or "16-methyl-16-phenyl- or 16-(substituted phenyl)-18,19,20-trinor" compounds respectively.

When R₇ is benzyl, the compounds so described are named as "17-phenyl-18,19,20-trinor" compounds. When R₇ is substituted phenylmethyl, the corresponding compounds are named as "17-(substituted phenyl)-18,19,20-trinor" compounds.

When R₇ is phenylethyl, the compounds so described are named as "18-phenyl-19,20-dinor" compounds. When R₇ is substituted benzyl, the corresponding compounds are named as "18-(substituted phenyl)-19,20-dinor" compounds.

When R₇ is phenylpropyl, the compounds so described are named as "19-phenyl-20-nor" compounds. When R₇ is substituted phenylpropyl the corresponding compounds are named as "19-(substituted phenyl)-20-nor" compounds.

When R₇ is phenoxy and neither R₃ nor R₄ is methyl, the compounds so described are named as "16-phenoxy-17,18,19,20-tetranor" compounds. When R₇ is substituted phenoxy, the corresponding compounds are named as "16-(substituted phenoxy)-17,18,19,20-tetranor" compounds. When one and only one of R₃ and R₄ is methyl or both R₃ and R₄ are methyl, then the corresponding compounds wherein R₇ is as defined in this paragraph are named as "16-phenoxy or 16-(substituted phenoxy)-18,19,20-trinor" compounds or "16-methyl-16-phenoxy- or 16-(substituted phenoxy)18,19,20-trinor" compounds, respectively.

Wherein R₇ is cis-CH═CH--CH--CH₂ CH₃, the compounds so described are named as "cis-17,18-didehydro-CBA" compounds.

When R₇ is --(CH₂)₂ --CH(OH)--CH₃, the compounds so described are named as "19-hydroxy-CBA" compounds.

When at least one of R₃ and R₄ is not hydrogen then (except for the 16-phenoxy or 16-phenyl compounds discussed above) there are described the "16-methyl" (one and only one of R₃ and R₄ is methyl), "16,16-dimethyl" (R₃ and R₄ are both methyl), "16-fluoro" (R₃ or R₄ is fluoro), "16,16-difluoro" (R₃ and R₄ are both fluoro) compounds. For those compounds wherein R₃ and R₄ are different, the prostaglandin analogs so represented contain an asymmetric carbon atom at C-16. Accordingly, two epimeric configurations are possible: "(16S)" and "(16R)". Further, there is described by this invention the C-16 epimeric mixture: "(16RS)".

When X₁ is --CH₂ OH, the compounds so described are named as "2-decarboxy-2-hydroxymethyl" compounds.

When X₁ is --CH₂ NL₂ L₃, the compounds so described are named as "2-decarboxy-2-aminomethyl" or "2-(substituted amino)methyl" compounds.

When X₁ is --COL₄, the novel compounds herein are named as CBA-type amides. Further, when X₁ is --COOR₁, the novel compounds herein are named as CBA-type esters and CBA-type salts.

Examples of phenyl esters substituted in the para position (i.e., X₁ is --COOR₁, R₁ is p-substituted phenyl) include p-acetamidophenyl ester, p-benzamidophenyl ester, p-(p-acetamidobenzamido)phenyl ester, p-(p-benzamidobenzamido)phenyl ester, p-amidocarbonylaminophenyl ester, p-acetylphenyl ester, p-benzylphenyl ester, p-amidocarbonylphenyl ester, p-methoxycarbonylphenyl ester, p-benzoyloxyphenyl ester, p-(p-acetamidobenzoyloxy)phenyl ester, and p-hydroxybenzaldehyde semicarbazone ester.

Examples of novel amides herein (i.e., X₁ is --COL₄) include the following:

(1) Amides within the scope of alkylamino groups of the formula-NR₂₁ R₂₂ are methylamide, ethylamide, n-propylamide, n-butylamide, n-pentylamide, n-hexylamide, n-heptylamide, n-octylamide, n-nonylamide, n-decylamide, n-undecylamide, and n-dodecylamide, and isomeric forms thereof. Further examples are dimethylamide, diethylamide, di-n-propylamide, di-n-butylamide, methylethylamide, methylpropylamide, methylbutylamide, ethylpropylamide, ethylbutylamide, and propylbutylamide. Amides within the scope of cycloalkylamino are cyclopropylamide, cyclobutylamide, cyclopentylamide, 2,3-dimethylcyclopentylamide, 2,2-dimethylcyclopentylamide, 2-methylcyclopentylamide, 3-tert-butylcyclopentyl amide, cyclohexylamide, 4-tert-butylcyclohexylamide, 3-isopropylcyclohexylamide, 2,2-dimethylcyclohexylamide, cycloheptylamide, cyclooctylamide, cyclononylamide, cyclodecylamide, N-methyl-N-cyclobutylamide, N-methyl-N-cyclopentylamide. N-methyl-N-cyclohexylamide, N-ethyl-N-cyclopentylamide, and N-ethyl-N-cyclohexylamide. Amides within the scope of aralkylamino are benzylamide, 2-phenylethylamide, and N-methyl-N-benzyl-amide. Amides within the scope of substituted phenylamide are p-chloroanilide, m-chloranilide, 2,4-dichloroanilide, 2,4,6-trichloroanilide, m-nitroanilide, p-nitroanilide, p-methoxyanilide, 3,4-dimethoxyanilide, 3,4,5-trimethoxyanilide, p-hydroxymethylanilide, p-methylanilide, m-methyl anilide, p-ethylanilide, t-butylanilide, p-carboxyanilide, p-methoxycarbonyl anilide, p-carboxyanilide and o-hydroxyanilide. Amides within the scope of carboxyalkylamino are carboxyethylamide, carboxypropylamide and carboxymethylamide, carboxybutylamide. Amides within the scope of carbamoylalkylamino are carbamoylmethylamide, carbamoylethylamide, carbamoylpropylamide, and carbamoylbutylamide. Amides within the scope of cyanoalkylamino are cyanomethylamide, cyanoethylamide, cyanopropylamide, and cyanobutylamide. Amides within the scope of acetylalkylamino are acetylmethylamide, acetylethylamide, acetylpropylamide, and acetylbutylamide. Amides within the scope of benzoylalkylamino are benzoylmethylamide, benzoylethylamide, benzoylpropylamide, and benzoylbutylamide. Amides within the scope of substituted benzoylalkylamino are p-chlorobenzoylmethylamide, m-chlorobenzoylmethylamide, 2,4-dichlorobenzoylmethylamide, 2,4,6-trichlorobenzoylmethylamide, m-nitrobenzoylmethylamide, p-nitrobenzoylmethylamide, p-methoxybenzoylmethylamide, 2,4-dimethoxy benzoylmethylamide, 3,4,5-trimethoxybenzoylmethylamide, p-hydroxymethylbenzoylmethylamide, p-methylbenzoylmethylamide, m-methylbenzoylmethylamide, p-ethylbenzoylmethylamide, t-butylbenzoylmethylamide, p-carboxybenzoylmethylamide, m-methoxycarbonylbenzoylmethylamide, o-carboxybenzoylmethylamide, o-hydroxybenzoylmethylamide, p-chlorobenzoylethylamide, m-chlorobenzoylethylamide, 2,4-dichlorobenzoylethylamide, 2,4,6-trichlorobenzoylethylamide, m-nitrobenzoylethylamide, p-nitrobenzoylethylamide, p-methoxybenzoylethylamide, p-methoxybenzoylethylamide, 2,4-dimethoxybenzoylethylamide, 3,4,5-trimethoxybenzoylethylamide, p-hydroxymethylbenzoylethylamide, p-methylbenzoylethylamide, m-methylbenzoylethylamide, p-ethylbenzoylethylamide, t-butylbenzoylethylamide, p-carboxybenzoylethylamide, m-methoxycarbonylbenzoylethylamide, o-carboxybenzoylethylamide, o-hydroxybenzoylethylamide, p-chlorobenzoylpropylamide, m-chlorobenzoylpropylamide, 2,4-dichlorobenzoylpropylamide, 2,4,6-trichlorobenzoylpropylamide, m-nitrobenzoylpropylamide, p-nitrobenzoylpropylamide, p-methoxybenzoylpropylamide, 2,4-dimethoxybenzoylpropylamide, 3,4,5-trimethoxybenzoylpropylamide, p-hydroxymethylbenzoylpropylamide, p-methylbenzoylpropylamide, m-methylbenzoylpropylamide, p-ethylbenzoylpropylamide, t-butylbenzoylpropylamide, p-carboxybenzoylpropylamide, m-methoxycarbonylbenzoylpropylamide, o-carboxybenzoylpropylamide, o-hydroxybenzoylpropylamide, p-chlorobenzoylbutylamide, m-chlorobenzoylbutylamide, 2,4-dichlorobenzoylbutylamide, 2,4,6-trichlorobenzoylbutylamide, m-nitrobenzoylmethylamide, p-nitrobenzoylbutylamide, p-methoxybenzoylbutylamide, 2,4-dimethoxybenzoylbutylamide, 3,4,5-trimethoxybenzoylbutylamide, p-hydroxymethylbenzoylbutylamide, p-methylbenzoylbutyamide, m-methylbenzoylbutylamide, p-ethylbenzoylbutyalmide, m-methylbenzoylbutylamide, p-ethylbenzoylbutylamide, t-butylbenzoylbutylamide, p-carboxybenzoylbutylamide, m-methoxycarboxybenzoylbutylamide, o-carboxybenzoylbutylamide, o-hydroxybenzoylmethylamide. Amides within the scope of pyridylamino are α-pyridylamide, β-pyridylamide, and γ-pyridylamide. Amides within the scope of substituted pyridylamino are 4-methyl-α-pyridylamide, 4-methyl-β-pyridylamide, 4-chloro-α-pyridylamide, and 4-chloro-β-pyridylamide. Amides within the scope of pyridylalkylamino are α-pyridylmethylamide, β-pyridylmethylamide, γ-pyridylmethylamide, α-pyridylethylamide, β-pyridylethylamide, γ-pyridylethylamide, α-pyridylpropylamide, β-pyridylpropylamide, γ-pyridylpropylamide, α-pyridylbutylamide, β-pyridylbutylamide, and γ-pyridylbutylamide. Amides within the scope of substituted pyridylalkylamido are 4-methyl-α-pyridylmethylamide, 4-methyl-β-pyridylmethylamide, 4-chloro-α-pyridylmethylamide, 4-chloro-β-pyridylmethyl-amide, 4-methyl-α-pyridylpropylamide, 4-methyl-β-pyridylpropylamide, 4-chloro-α-pyridylpropylamide, 4-chloro-β-pyridylpropylamide, 4-methyl-α-pyridylbutylamide, 4-methyl-β-pyridylbutylamide, 4-chloro-α-pyridylbutylamide, 4-chloro-β-pyridylamide, 4-chloro-γ-pyridylbutylamide. Amides within the scope of hydroxyalkylamino are hydroxymethylamide, α-hydroxyethylamide, β-hydroxyethylamide, α-hydroxypropylamide, β-hydroxypropylamide, γ-hydroxypropylamide, 1-(hydroxymethyl)ethylamide, 1-(hydroxymethyl)propylamide, (2-hydroxymethyl)propylamide, and α,α-dimethyl-hydroxyethylamide. Amides within the scope of dihydroxyalkylamino are dihydroxymethylamide, α,α-dihydroxyethylamide, α,β-dihydroxyethylamide, β,β-dihydroxyethylamide, α,α-dihydroxypropylamide, α,β-dihydroxypropylamide, α,γ-dihydroxypropylamide, β,β-dihydroxypropylamide, β,γ-dihydroxypropylamide, γ,γ-dihydroxypropylamide, 1-(hydroxymethyl)-2-hydroxymethylamide, 1-(hydroxymethyl)-1-hydroxyethylamide, α,α-dihydroxybutylamide, α,β-dihydroxybutylamide, α,γ-dihydroxybutylamide, α,δ-dihydroxybutylamide, β,β-dihydroxybutylamide, β,γ-dihydroxybutylamide, β,δ-dihydroxybutylamide, γ,γ-dihydroxybutylamide, γ,δ-dihydroxybutylamide, δ,δ-dihydroxybutylamide, and 1,1-bis(hydroxymethyl)ethylamide. Amides within the scope of trihydroxyalkylamino are tris(hydroxymethyl)methylamide and 1,3-dihydroxy-2-hydroxymethylpropylamide.

(2) Amides within the scope of cycloamino groups described above are pyrrolidylamide, piperidylamide, morpholinylamide, hexamethyleneiminylamide, piperazinylamide, pyrrolinylamide, and 3,4-didehydropiperidinylamide.

(3) Amides within the scope of carbonylamino of the formula --NR₂₃ COR₂₁ are methylcarbonylamide, ethylcarbonylamide, phenylcarbonylamide, and benzylcarbonylamide.

(4) Amides within the scope of sulfonylamino of the formula --NR₂₃ SO₂ R₂₁ are methylsulfonylamide, ethylsufonylamide, phenylsulfonylamide, p-tolylsulfonylamide, benzylsulfonylamide.

Examples of alkyl of one to 12 carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, isomeric forms thereof.

Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive, which includes alkyl-substituted cycloalkyl, are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

Examples of aralkyl of 7 to 12 carbon atoms, inclusive, are benzyl, 2-phenylethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-(1-naphthylethyl), and 1-(2-naphthylmethyl).

Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, are p-chlorophenyl, m-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl, p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.

Examples of substituted phenoxy, phenylmethyl, phenylethyl, or phenylpropyl of the R₇ moiety are (o-, m-, or p-)tolyl, (o-, m-, or p-(ethylphenyl, 2-ethyltolyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, (o-, m-, or p-)propylphenyl, 2-propyl-(o-, m-, or p-)tolyl, 4-isopropyl-2,6xylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)trimethylphenyl, (p-, m-, or p-)fluorophenyl, 2-fluoro-(o-,m-, or p-)tolyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)-difluorophenyl, (o-,m-, or p-)chlorophenyl, 2-chloro-p-tolyl, (3-, 4-, 5-, or 6-)chloro-o-tolyl, 4-chloro-2-propylphenyl, 2-isopropyl-4-chlorophenyl, 4-chloro-3,5-xylyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenyl, 4-chloro-3-fluorophenyl, (3- or 4-)chloro-2-fluorophenyl, (o-, m-, or p-)trifluoromethylphenyl, (o-, m-, or p-)-methoxyphenyl, (o-, m-, or p-)ethoxyphenyl, (4- or 5-)chloro-2-methoxyphenyl, 2,4-dichloro-(4- or 6-)methylphenyl, (o-, m-, or p-)-tolyloxy, (o-, m-, or p-)ethylphenyloxy, 2-ethyltolyloxy, 4-ethyl-o-tolyloxy, 5-ethyl-m-tolyloxy, (o-, m-, or p-)propylphenoxy, 2-propyl-(o-, m-, or p-)tolyloxy, 4isopropyl-2,6-xylyloxy, 3-propyl-4-ethylphenyloxy, (2,3,4 -, 2,3,5-, 2,3,6-, or 2,4,5-)trimethylphenoxy, (o-, m-, or p-)fluorophenoxy, 2-fluoro-(o-, m-, or p-)tolyloxy, 4-fluoro-2,5-xylyloxy, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenoxy, (o-, m-, or p-)-chlorophenoxy, 2-chloro-p-tolyloxy, (3, 4, 5, or 6-)chloro-o-tolyloxy, 4-chloro-2-propylphenoxy, 2-isopropyl-4-chlorophenoxy, 4-chloro-3,5-xylyloxy, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenyloxy, 4-chloro-3-fluorophenoxy, (3- or 4-)chloro-2-fluorophenoxy, (o-, m-, or p-)trifluoromethylphenoxy, (o-, m-, or p-)-methoxyphenoxy, (o-, m-, or p-)ethoxyphenoxy, (4- or 5-)chloro-2-methoxyphenoxy, 2,4-dichloro-(5- or 6-)methylphenoxy, (o-, m-, or p-)tolylmethyl, (o-, m-, or p-)ethylphenyl methyl, 2-ethyltolylmethyl, 4-ethyl-o-tolylmethyl, 5-ethyl-m-tolylmethyl, (o-, m-, or p-)propylphenylmethyl, 2-propyl-(o-, m-, or p-)tolylmethyl, 4-isopropyl-2,6-xylylmethyl, 3-propyl-4-ethylphenylmethyl, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)trimethylphenylmethyl, (o-, m-, or p-)fluorophenylmethyl, 2-fluoro-(o-, m-, or p-)tolylmethyl, 4-fluoro- 2,5-xylylmethyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenyl, (o-, m-, or p-)chlorophenylmethyl, 2-chloro-p-tolymethyl, (3, 4, 5, or 6-)chloro-o-tolylmethyl, 4-chloro-2-propylphenylmethyl, 2-isopropyl-4-chlorophenylmethyl, 4-chloro-3,5-xylylmethyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenylmethyl, 4-chloro-3-fluorophenyl, (3- or 4-)chloro2-fluorophenylmethyl, (o-, m-, or p-)trifluoromethylphenylmethyl, (o-, m-, or p-)methoxyphenylmethyl, (o-, m-, or p-)ethoxyphenylmethyl, (4- or 5-)chloro-2-methoxyphenylmethyl, and 2,4-dichloro-(4- or 6-)methoxyphenylmethyl.

The novel CBA₂ analogs of the present invention are all surprisingly unexpectedly highly active pharmacological agents, being useful for the pharmacological purposes for which CBA₂ is employed. Thus, preferred among the useful pharmacological uses of the instant CBA analogs is the inhibition of platelet aggregation in mammalian species, especially humans. For example, these novel CBA analogs are useful in accomplishing reduction of the adhesive character of platelets and the removal or prevention of the formation of platelet thrombi. Accordingly, these pharmacological actions give numerous clinical and veterinary uses of the novel CBA analogs, including the treatment and prevention of myocardial infarction and cerebral ishemic attacks, treatment and prevention of post-operative thrombosis and facilitation of storage of blood and blood platelets.

In accomplishing the clinical or veterinary uses of the novel CBA analogs, they are employed at dosages or concentrations and by methods and routes of administration at which prostacyclin is employed. However, the novel compounds herein are much more advantageously used for these purposes than prostacyclin inasmuch as they show more selectivity of action. For example, when used as platelet anti-aggregatory agents, they accomplish this function in vivo with fewer and less intense cardiovascular side effects, e.g., hypotensive effects.

The formula IV--VI CBA intermediates are all useful in preparing either the known CBA compounds or the novel CBA analogs of formula VII.

When X₁ is --COOR₁, the novel CBA analogs so described are used for the purposes described above in the free acid form, in ester form, in pharmacologically acceptable salt form. When the ester form is used, the ester is any of those within the above definition of R₁. However, it is preferred that the ester be alkyl of one to 12 carbon atoms, inclusive. Of the alkyl esters, methyl and ethyl are especially preferred for optimum absorption of the compound by the body or experimental animal system; and straight-chain octyl, nonyl, decyl, undecyl, and dodecyl are especially preferred for prolonged activity.

Pharmacologically acceptable salts of the novel prostaglandin analogs of this invention for the purposes described above are those with pharmacologically acceptable metal cations, ammonia, amine cations, or quaternary ammonium cations.

Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium, and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary, and tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine, ethylenediamine, diethylenetriamine, and the like aliphatic, cycloaliphatic, araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereto, ,e.g., 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like as well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris(hydroxymethyl) aminomethane, N-phenylethanolamine, N-(p-tert-amylphenyl)-diethanolamine, galactamine, N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like. Further useful amine salts of the basic amino acid salts, e.g., lysine and arginine.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like.

When X₁ is --CH₂ NL₂ L₃, the novel CBA analogs so described are used for the purposes described in either free base or pharmacologically acceptable acid addition salt form.

The acid addition salts of the 2-decarboxy-2-aminomethyl- or 2-(substituted aminomethyl)-CBA analogs provided by this invention are the hydrochlorides, hydrobromides, hydriodides, sulfates, phosphates, cyclohexanesulfamates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates and the like, prepared by reacting the CBA analog with the stoichiometric amount of the acid corresponding to the pharmacologically acceptable acid addition salt.

To obtain the optimum combination of biological response, specificity, potency, and duration of activity, certain compounds Within the scope of this invention are preferred.

It is preferred that in the X₁ -terminated side chain g be either one or 3, especially one, i.e., the chain length of CBA₂. Further, when the C-12 side chain contains --(CH₂)_(m) -CH₃, it is preferred that m be 3 or 4, most preferably 3. Further, it is preferred that, when R₇ is aromatic, R₇ be phenoxy, phenyl, or benzyl, including substituted forms thereof. For those compounds wherein R₇ is substituted phenoxy or phenylalkyl, it is preferred there be only one or 2 substituents selected from the group consisting of chloro, fluoro, or trifluoromethyl. Further, for those compounds wherein R₇ is aromatic, it is preferred that R₃ and R₄ both be hydrogen.

Expecially preferred are those compounds which satisfy two or more of the above preferences. Further, the above preferences are expressly intended to describe the preferred compounds within the scope of any generic formula of novel CBA analogs disclosed herein.

Those protective groups within the scope of R₁₀ are any group which replaces a hydroxy hydrogen and is neither attacked by nor as reactive to the reagents used in the transformations used herein as a hydroxy is and which is subsequently replaceable by acid hydrolysis with hydrogen in the preparation of the prostaglandin-type compounds. Several such protective groups are known in the art, e.g., tetrahydropyranyl and substituted tetrahydropyranyl. See for reference E. J. Corey, Proceedings of the Robert A. Welch Foundation Conferences on Chemical Research, XII Organic Synthesis, pgs. 51-79 (1969). Those blocking groups which have been found useful include:

(a) tetrahydropyranyl;

(b) tetrahydrofuranyl;

(c) a group of the formula --C(OR₁₁) (R₁₂)--CH(R₁₃) (R₁₄), wherein R₁₁ is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl or phenyl substituted with one to 3 alkyl of one to 4 carbon atoms, inclusive, wherein R₁₂ and R₁₃ are alkyl of one to 4 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2 or 3 alkyl of one to 4 carbon atoms, inclusive, or when R₁₂ and R₁₃ are taken together --(CH₂)_(a) -- or when R₁₂ are R₁₃ are taken together --(CH₂)_(b) --O--(CH₂)_(c), wherein a is 3, 4, or 5 and b is one, 2, or 3, and c is one, 2, or 3, with the proviso that b plus c is 2, 3, or 4, with the further proviso that R₁₂ and R₁₃ may be the same or different, and wherein R₁₄ is hydrogen or phenyl; and

(d) Silyl groups according to R₂₈.

When the blocking group R₁₀ is tetrahydropyranyl, the tetrahydropyranyl ether derivative of any hydroxy moieties of the CBA-type intermediates herein is obtained by reaction of the hydroxy-containing compound with 2,3-dihydropyran in an inert solvent, e.g., dichloromethane, in the presence of an acid condensing agent such as p-toluenesulfonic acid or pyridine hydrochloride. The dihydropyran is used in large stoichiometric excess, preferably 4 to 100 times the stoichiometric amount. The reaction is normally complete in less than an hour at 20°-50° C.

When the protective group is tetrahydrofuranyl, 2,3-dihydrofuran is used, as described in the preceding paragraph, in place of the 2,3-dihydropyran.

When the protective group is of the formula --C(OR₁₁) (R₁₂)--CH(R₁₃) (R₁₄), wherein R₁₁, R₁₂, R₁₃, and R₁₄ are as defined above; a vinyl ether or an unsaturated cyclic or heterocyclic compound, e.g., 1-cyclohexen-1-yl methyl ether, or 5,6-dihydro-4-methoxy-2H-pyran is employed. See C. B. Reese, et al., Journal of the Chemical Society 86, 3366 (1967). The reaction conditions for such vinyl ethers and unsaturated compounds are similar to those for dihydropyran above.

R₂₈ is a silyl protective group of the formula -Si(G₁)₃. In some cases, such silylations are general, in that they silylate all hydroxyls of a molecule, while in other cases they are selective, in that while one or more hydroxyls are silylated, at least one other hydroxyl remains unaffected. For any of these silylations, silyl groups within the scope of -Si(G₁)₃ include trimethylsilyl, dimethylphenylislyl, triphenylsilyl, t-butyldimethylsilyl, or methylphenylbenzylsilyl. With regard to G₁, examples of alkyl are methyl, ethyl, propyl, isobutyl, butyl, sec-butyl, tert-butyl, pentyl, and the like. Examples of aralkyl are benzyl, phenethyl, α-phenylethyl, 3-phenylpropyl, α-naphthylmethyl, and 2-(α-naphthyl)ethyl. Examples of phenyl substituted with halo or alkyl are p-chlorophenyl, m-fluorophenyl, o-tolyl, 2,4-dichlorophenyl, p-tert-butylphenyl, 4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.

These silyl groups are known in the art. See for example, Pierce "Silylation of Organic Compounds, " Pierce Chemical Company, Rockford, Ill. (1968). When silylated products of the charts below are intended to be subjected to chromatographic purification, then the use of silyl groups known to be unstable to chromatography (e.g. trimethylsilyl) is to be avoided. Further, when silyl groups are to be introduced selectively, silylating agents which are readily available and known to be useful in selective silylations are employed. For example, trimethylsilyl, triphenylsilyl and t-butyldimethylsilyl groups are employed when selective introducing is required. Further, when silyl groups are to be selectively hydrolyzed in the presence of protective groups according to R₁₀ or acyl protective groups, then the use of silyl groups which are readily available and known to be easily hydrolyzable with tetra-n-butylammonium fluoride are employed. A particularly useful silyl group for this purpose is t-butyldimethylsilyl, although other silyl groups (e.g. trimethylsilyl) are likewise employed.

The protective groups as defined by R₁₀ are otherwise removed by mild acidic hydrolysis. For example, by reaction with (1) hydrochloric acid in methanol; (2) a mixture of acetic acid, water, and tetrahydrofuran, or (3) aqueous citric acid or aqueous phosphoric acid in tetrahydrofuran, at temperatures below 55° C., hydrolysis of the blocking group is achieved.

R₃₁ is hydroxy-hydrogen protective group, as indicated above. As such, R₃₁ may be an acyl protective group according to R₉, an acid hydrolyzable protective group according to R₁₀, a silyl protective group according to R₂₈, or an arylmethyl hydroxy hydrogen replacing group according to R₃₄.

Acyl protective groups according to R₉ include:

(a) benzoyl;

(b) benzoyl substituted with one to 5 alkyl of one to 4 carbon atoms, inclusive, or phenylalkyl of 7 to 12 carbon atoms, inclusive, or nitro, with the proviso that not more than two substituents are other than alkyl, and that the total number of carbon atoms in the substituents does not exceed 10 carbon atoms, with the further proviso that the substituents are the same or different;

(c) benzoyl substituted with alkoxycarbonyl of 2 to 5 carbon atoms, inclusive;

(d) naphthoyl;

(e) naphthtoyl substituted with one to 9, inclusive, alkyl of one to 4 carbon atoms, inclusive, phenylalkyl of 7 to 10 carbon atoms, inclusive, or nitro, with the proviso that not more than two substituents on either of the fused aromatic rings are other than alkyl and that the total number of carbon atoms in the substituents on either of the fused aromatic rings does not exceed 10 carbon atoms, with the further proviso that the various substituents are the same or different; or

(f) alkanoyl of 2 to 12 carbon atoms, inclusive.

In preparing these acyl derivatives of a hydroxy-containing compound herein, methods generally known in the art are employed. Thus, for example, an aromatic acid of the formula R₉ OH, wherein R₉ is as defined above (e.g., benzoic acid), is reacted with the hydroxy-containing compound in the presence of a dehydrating agent, e.g. p-toluensulfonyl chloride or dicyclohexylcarbodiimide; or alternatively an anhdride of the aromatic acid of the formula (R₉)OH, e.g., benzoic anhydride, is used.

Preferably, however, the process described in the above paragraph proceeds by use of the appropriate acyl halide, e.g., R₉ Hal, wherein Hal is chloro, bromo, or iodo. For example, benzoyl chloride is reacted with the hydroxy-containing compound in the presence of a hydrogen chloride scavenger, e.g. a tertiary amine such as pyridine, triethylamine or the like. The reaction is carried out under a variety of conditions, using procedures generally known in the art. Generally mild conditions are employed: 0°-60° C., contacting the reactants in a liquid medium (e.g., excess pyridine or an inert solvent such as benzene, toluene, or chloroform). The acylating agent is used either in stoichiometric amount or in substantial stoichiometric excess.

As examples of R₉, the following compounds are available as acids (R₉ OH), (R₉)₂ O, or acyl chlorides (R₉ Cl): benzoyl; substituted benzoyl, e.g., (2-, 3-, or 4-)methylbenzoyl, (2-, 3-, or 4-)ethylbenzoyl, (2-, 3-, or 4-)isopropylbenzoyl, (2-, 3-, or 4-)tert-butylbenzoyl, 2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyltoluyl, 2,4,6-trimethylbenzoyl, pentamethylbenzoyl, phenyl(2-, 3-, or 4-)toluyl, (2-, 3-, or 4-)phenethylbenzoyl, (2-, 3-, or 4-)nitrobenzoyl, (2,4, 2,5-, or 2,3-)dinitrobenzoyl, 2,3-dimethyl-2-nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl, 2-nitro-6-phenylethylbenzoyl, 3-nitro-2-phenethylbenzoyl, 2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl; mono esterified phthaloyl, isophthaloyl, or terephthaloyl; 1- or 2-naphthoyl; substituted naphthoyl, e.g., (2-, 3-, 4-, 5-, 6-, or 7-)methyl-1-naphthoyl, (2- or 4-)ethyl-1-naphthoyl, 2-isopropyl-1-naphthoyl, 4,5-dimethyl-1-naphthoyl, 6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl, (3-, 4-, 5-, or 8-)-nitro-1-naphthoyl, 4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7-, or 8-)methyl-1-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or 8-)nitro-2-naphthoyl and acetyl.

There may be employed, therefore, benzoyl chloride, 4-nitrobenzoyl chloride, 3,5-dinitrobenzoyl chloride, or the like, i.e. R₉ Cl compounds corresponding to the above R₉ groups. If the acyl chloride is not available, it is prepared from the corresponding acid and phosphorus pentachloride as is known in the art. It is preferred that the R₉ OH, (R₉)₂ O, or R₉ Cl reactant does not have bulkyl hindering substituents, e.g., tert-butyl on both of the ring carbon atoms adjacent to the carbonyl attaching site.

The acyl protective groups, according to R₉, are removed by deacylation. Alkali metal carbonate or hydroxide are employed effectively at ambient temperature for this purpose. For example, potassium carbonate or hydroxide in aqueous methanol at about 25° C. is advantageously employed.

R₃₄ is defined as any arylmethyl group which replaces the hydroxy hydrogen of the intermediates in the preparation of the various CBA analogs herein which is subsequently replaceable by hydrogen in the processes herein for preparation of these respective prostacyclin analogs, being stable with respect to the various reactions to which R₃₄ -containing compounds are subjected and being introduced and subsequently removed by hydrogenolysis under conditions which yield substantially quantitative yields of desired products.

Examples of arylmethyl hydroxy-hydrogen replacing groups are

(a) benzyl;

(b) benzyl substituted by one to 5 alkyl of one to 4 carbon atoms, inclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12 carbon atoms, inclusive, with the further proviso that the various substituents are the same or different;

(c) benzhydryl;

(d) benzhydryl substituted by one to 10 alkyl of one to 4 carbon atoms, inclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12 carbon atoms, inclusive, with the further proviso that the various substituents are the same or different on each of the aromatic rings;

(e) trityl;

(f) trityl substituted by one to 15 alkyl of one to 4 carbon atoms, inclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12 carbon atoms, inclusive, with the further proviso that the various substituents are the same or different on each of the aromatic rings.

The introduction of such ether linkages to the hydroxy-containing compounds herein, particularly the benzyl or substituted benzyl ether proceeds by methods known in the art, for example by reaction of the hydroxy-containing compound with the benzyl or substituted benzyl halide (chloride, bromide, or iodide) corresponding to the desired ether. This reaction proceeds in the presence of an appropriate condensing agent (e.g., silver oxide). The mixture is stirred and heated to 50°-80° C. Reaction times of 4 to 20 hours are ordinarily sufficient.

The Charts herein describe the methods whereby the novel intermediates and end products of the present specification are prepared by the novel processes herein. With respect to these charts, n, R₁₈, Y₁, M₁, M₆, L₁, R₇, R₂₈, Z₁, X₁, R₃₁ are as defined above. R₃₈ is --OR₃₁, hydrogen, or --CH₂ OR₃₁, wherein R₃₁ is defined as above.

With respect to Chart A, a method is provided whereby the known formula XXI bicyclic lactone is transformed to the known carbacyclin intermediate of formula XXV. With respect to Chart A, the formula XXI compound is transformed to the formula XXII compound by treatment with the anion of dimethyl methylphosphonate. Methods for such a reaction are known in the art. See Dauben, W. G., et al., JACS, 97:4973 (1975), describing a reaction of this type.

The formula XXII lactol is transformed to the formula XXIII diketone by oxidation methods known in the art. For example, Collins reagent or Jones reagent is employed in this oxidative transformation.

The formula XXIII diketone is cyclized to the formula XXIV compound by an intramolecular Horner-Emmons reaction. The chemical methodology for analogous transformations is known in the art. See Piers, E., et al., Tetrahedron Letters, 3279 (1979) and Clark, R. D., et al., Synthetic Communications 5:1 (1975).

The formula XXIV compound is then transformed to the formula XXV compound by reduction. Such reductions are performed either by catalytic means (e.g., catalytic hydrogenation), or by employing an alkaline earth metal. However, the preferred method is to employ the procedure of Cortese, N. A. and Heck, R. F., J. Org. Chem. 43:3985 (1978), e.g., the use of triethylammonium formate and a palladium catalyst.

With respect to Chart B, a method is provided whereby the formula XXXI compound prepared in accordance with methods of Chart A is transformed to the novel CBA₂ analogs of formula XXXVI.

The formula XXXI compound is transformed to the formula XXXVI compound by methods known in the art for preparing carbacyclin. See for example, British published applications referred to above. Alternatively, the formula XXXI compound is reacted with formula XXXII compound and thereby successively transformed to the formula XXXIII, formula XXXIV and formula XXXV compounds.

The reaction of the formula XXXI compound employing the formula XXXII compound is accomplished by methods known in the art. See Moersch, G. W., J. Organic Chemistry, 36:1149 (1971) and Mulze, J., et al., Tetrahedron Letters, 2949 (1978). The formula XXXII reactants are known in the art or are prepared by methods known in the art. See Example 4 describing one such method of preparation of a formula XXXII compound.

The formula XXXIII compound is then transformed to the formula XXXIV compound by decarboxylative dehydration. Procedures for this reaction are known in the art. See Eschenmoser, A., et al., Helv. Chim. Acta. 58:1450 (1975), Hara, S., et al., Tetrahedron Letters, 1545 (1975) and Mulzer, J., et al., Tetrahedron Letters, 2953 (1978) and 1909 (1979).

Finally, the Formula XXXV compound is prepared from formula XXXIV compound by selective desilylation. Such procedures are known in the art and typically employ the use of tetra-n-butyl ammonium fluoride and tetrahydrofuran. See Corey, E. J., et al., JACS 94:6190 (1972).

Thereafter, the formula XXXV compound is transformed to various acids, esters, amides, and amines of formula XXXVI by methods known in the art. Particularly useful in this regard are methods described in the aforementioned British published specifications describing the preparation of carbacyclin analogs.

The preparation of formula XXXVI compounds from the formula XXXV compounds proceeds by, for example, oxidation to the corresponding carboxylic acid, followed by hydrolysis of any protective groups at the C-11 or C-15 position of the molecule. Such carboxylic acids are then esterified by conventional means or amidized by conventional means. Such amides may, for example, then be reduced to corresponding amines (X₁ is --CH₂ NL₂ L₃ by reduction by lithium aluminum hydride. See U.S. Pat. No. 4,073,808. In a preparation of the primary alcohols according to formula XXXVI from the formula XXXV compound, hydrolysis of any protective groups at C-11 or C-15 yields such products directly. Hydrolysis is accomplished by procedures described above, e.g., mild acidic conditions at elevated temperatures.

Chart C provides a method whereby the known formula XLI compound is transformed into formula XLIII intermediate useful in the preparation of the novel compounds in accordance with the instant invention.

The procedures for the transformation of the formula XLI compound to the formula XLIII compound are analogous to those describing the transformation in Charts A and B of the formula XXI compound to the formula XXXVI compound (i.e., corresponding to the transformation of formula XLI compound to the formula XLII compound is the transformation in Chart A of the formula XXI compound to the formula XXIV compound). For convenience, the protective groups R₃₁ and R₃₈ may be the same or different, although preferably such protective groups are different, whereby the hydrolysis of a protective group according to R₃₁ is accomplished in the presence of a protective group according to R₃₈.

Chart D then provides a method whereby the formula LI compound prepared according to Chart A is transformed to the formula LII carbacyclin intermediate in accordance with the present invention. With respect to Chart D, the formula LI compound is transformed to the formula LII compound by selective hydrolysis of the protective group according to R₃₁. Thereafter, the formula LII compound is transformed to formula LIII compound by methods known in the art, e.g., oxidation of the formula LII primary alcohol to the corresponding aldehyde, Wittig oxylacylating the aldehyde, and reduction of the resulting ketone to the secondary or tertiary alcohol corresponding to M₁. For an example of the various transformations employed according to Chart D, see Chart A (part VI) of U.S. Pat. No. 4,107,427, issued Aug. 15, 1978.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is more clearly understood by the operation of the following examples:

EXAMPLE 1 3-oxo-7α-tetrahydropyran-2-yloxy-6β[(3'S)-3'-tetrahydropyran-2-yloxy-trans-1'-octenyl]-bicyclo[3.3.0]-oct-1-ene (Formula XXIV: R₁₈ is tetrahydropyranyloxy; Y₁ is trans-CH═CH--, M₆ is α-tetrahydropyranyloxy β:--H, L₁ is α-H:β-H, R₇ is n-butyl; and n is the integer one).

Refer to Chart A.

A. To a stirred solution of 19 ml (170 mmoles) dimethyl methylphosphonate and 600 ml of dry tetrahydrofuran at -78° C. under an argon atmosphere is added dropwise over 5 minutes 110 ml (172 mmoles) of 1.56 M n-butyllithium in hexane. The resulting solution is stirred for 30 minutes at -78° C., treated with 25.4 g of 3α,5α-dihydroxy-2β-(3α-hydroxy-trans-1-octenyl)-1.alpha.-cyclopentaneacetic acid, lactone, (bis(tetrahydropyranyl)ether, in 100 ml of dry tetrahydrofuran dropwise over one hour, and stirred for one hour at -78° C. and four hours at room temperature. The reaction is then quenched by addition of 10 ml glacial acetic acid, diluted with 700 ml of brine, and extracted with diethyl ether (3×700 ml). The combined ethereal layers was washed with 200 ml bicarb and 500 ml brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 37 g of formula XXII compound as oily white solid: 3-dimethylphosphonomethyl-3-hydroxy-2-oxa-7α-tetrahydropyran-2-yloxy-6β[(3'S)-3'-tetrahydropyran-2-yloxy-trans-1'-octenyl]-bicyclo[3.3.0]octane. Crystallization of the crude product from hexane and ether yields 22.1 g of purified formula XXII product. Silica gel TLC Rf is 0.22 in ethyl acetate. The melting range is 89°-93° C. NMR absorptions are observed at 3.72 (doublet, J=11 Hz) and 3.83 (doublet, J=11 Hz)δ. Characteristic infrared absorptions are 3340, 1250, 1185, 1130, 1075, and 1030 cm⁻¹.

B. To a solution of 10.0 g of the product of Part A in 75 ml acetone stirring under a nitrogen atmosphere at -10° is added over 30 minutes 9.0 ml of Jones reagent. The resulting suspension is stirred for 30 minutes at -10° and then quenched with 4 ml 2-propanol. The solvents are decanted away from the green residue and most of the acetone removed at reduced pressure. The acetone concentrate is then taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure yields 8.2 g of formula XXIII product: 2-decarboxy-6-desbutyl-6-dimethylphosphonomethyl-6-keto-PGE₁ ; 11,15-bis(tetrahydropyranyl ether). Chromatography of formula XXIII product on 600 g silica gel eluting with 20% acetone in methylene chloride yields 4.95 g of pure formula XXIIII product. Silica gel TLC R_(f) (in 20% acetone in methylene chloride) is 0.22. Characteristic NMR absorptions are observed at 3.14 (doublet, J=23 Hz) and 3.80 (doublet, J=11 Hz), 5.4-5.8 (m)δ. Characteristic infrared absorptions are observed at 1745, 1715, 1260, 1200, 1185, 1130, 1030, 970, 870 cm⁻¹.

C. A suspension of 5.37 g of the product of Example 1, Part B, 1.33 g anhydrous potassium carbonate, and 5.37 g 18-Crown-6 ether in 200 ml toluene is heated at 75° for six hours under a nitrogen atmosphere, cooled to 0°, and wshed with 200 ml brine, 200 ml of 3:1 water:brine, and 200 ml brine, and dried over anhydrous sodium sulfate. Most of the solvents are removed under reduced pressure and the residue is filtered through 50 g silica gel eluting with 250 ml ethyl acetate to give 3.9 g of formula XXIV product: 3-oxo-7α-tetrahydropyranyl-2-yloxy-6β[(3'S)-3'-tetrahydropyran-2-yloxy-trans-1'-octenyl]bicyclo[3.3.0]oct-1-ene. The crude product is chromatographed on 300 g silica gel eluting with 60:40 hexane:ethyl acetate to give 2.39 g of pure formula XXIV product. Silica gel TLC R_(f) is 0.22 in 60:40 Hexane:ethyl acetate. NMR absorptions are observed at 5.18-5.86 (m) and 5.94 (broad singlet)δ. Infrared absorptions are observed at 1710 and 1632 cm⁻¹.

Following the procedure of Example 1, but employing the various 3α,5α-dihydroxy-2-substituted-1α-cyclopentaneacetic acid gamma lactones of formula XXI, there are prepared each of the various corresponding formula XXIV products wherein n is 1.

Further, following the procedure of Example 1, but employing each of the various 3α,5α-dihydroxy-2-substituted-1α-cyclopentanepriopionic acid, δ-lactones of formula XXI, there are prepared each of the various formula XXIV compounds wherein n is 2.

Further, following the procedure of Example 1, but employing each of the various 5α-hydroxy-2-substituted-1α-cyclopentanealkanoic acid lactones of formula XXI, there are prepared each of the various formula XXIV compounds wherein R₁₈ is hydrogen. Finally, following the procedure of Example 1, but employing each of the various 3α-hydroxymethyl-5α-hydroxy-2-substituted-1α-cyclopentanealkanoic acid lactones of formula XXI, there are prepared each of the various formula XXIV compounds wherein R₁₈ is --CH₂ OR₁₀.

EXAMPLE 2 3-oxo-8α-tetrahydropyran-2-yloxy-7β[(3'S)-3'-tetrahydropyran-2-yloxy-trans-1'-octenyl]bicyclo[4.3.0]non-1-ene (Formula XXIV: R₁₈, Y₁, M₆, R₇ are defined in Example 1 and n is the integer 2).

Refer to Chart A.

A. A solution of 2.05 ml (18.9 mmoles) of dimethyl methylphosphonate and 100 ml of dry tetrahydrofuran is stirred at -78° C. under a nitrogen atmosphere and treated dropwise with 11.8 ml (18.9 mmoles) of 1.6 molar n-butyllithium in hexane. After stirring for 30 minutes at -78° C., the resulting mixture is treated dropwise over 25 minutes with 4.25 g of 3α,5α-dihydroxy-2β-(3α-hydroxy-trans-1-octenyl) 1α-cyclopentane propionic acid, δ-lactone, 11,15-bis(tetrahydropyranyl ether), in 30 ml of dry tetrahydrofuran. The resulting mixture is then stirred for one hour at 78° C. The solution is then allowed to stir at ambient temperature for 2 hours and is quenched by addition of 1.2 ml of acetic acid. The mixture is then added to 250 ml of brine and 200 ml of diethyl ether. The aqueous and organic layers are then separated and the aqueous layer extracted twice with diethyl ether. The ethereal extracts are then washed with brine, dried over anhydrous sodium sulfate, and concentrated to yield 5.6 g of crude formula XXII compound, as an oil: 3-(dimethylphosphomethyl)-3-hydroxy-2-oxa-8α-tetrahydropyran-2-yl-oxy-7β[(3'S)-3'-tetrahydropyran-2-yloxy-trans-1'-octenyl]-bicyclo[4.3.0]nonane. Chromatography on silica gel eluting with 4:1 ethyl acetate:acetone yields 4.1 g of purified formula XXII product. Characteristic NMR absorption is observed at 5.15-5.65 (multiplet)δ. Silica gel TLC R_(f) is 0.34 in 4:1 ethyl acetate:acetone. Characteristic infrared absorptions are observed at 3350, 1235, and 1030 cm⁻¹.

B. A suspension of 3.42 g of chromium trioxide and 80 ml of methylene chloride is treated with 5.8 ml of pyridine, stirred at ambient temperature under a nitrogen atmosphere for 30 minutes, and combined with 3 scoops of dry diatomaceous earth. The resulting mixture is then treated with 3.25 g of the reaction product of Part A and 8 ml of dry dichloromethane, stirred for 30 minutes at ambient temperature under nitrogen, filtered through 30 g of silica gel (eluting with 200 ml of ethylacetate and acetone, 2:1) and concentrted under reduced pressure. Chromatographing the residue (3.73 g) on 120 g of silica gel, eluting with ethyl acetate and acetone (4:1) yields 2.07 g of formula XXIII product: 2-decarboxy-5-despropyl-5-dimethylphosphonomethyl-5-keto-PGE₁, 11,15-bis(tetrahydropyranyl ether). Characteristic infrared absorptions are observed at 1740 and 1715 cm⁻¹. Characteristic NMR absorptions are observed at 3.1 (doublet, J=23 Hz) and 3.8 (doublet, J=11 Hz)δ.

C. A suspension of 12 mg of 50% sodium hydride in mineral oil and 3 ml of diglyme is stirred at 0° C. under an argon atmosphere. The suspension is then treated with 150 mg of the product of Part B in 3 ml of diglyme. After 1 hour, the cooling bath is removed and the resulting solution is stirred at ambient temperature under argon. After a total of 20 hours from addition of the formula XXIII reactant, the resulting solution is then added to 30 ml of water and extracted with 90 ml of diethyl ether. The ethereal extract is washed with brine (30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure to a brown oil (110 mg) and chromatographed on 10 g of silica gel eluting with hexane and ethyl acetate (1:1). There is accordingly prepared 15 mg of formula XXIV compound: 3-oxo-8α-tetrahydropyran-2-yloxy-7β-[(3'S)-3'-tetrahydropyran-2-yloxy-trans-1' -octenyl]bicyclo[4.3.0]non-1-ene. NMR absorptions are observed at 4.7 (broad singlet) and 5.3-6.0 (multiple)δ. IR absorption is observed at 1670 cm⁻¹.

Alternatively, the formula XXIV compound above is prepared as follows:

A solution of 150 mg of the product of Part B and 5 ml of dry tetrahydrofuran at 0° C. under an argon atmosphere is treated dropwise with 0.5 ml of 0.52 M potassium hydride and 18-crown-6-ether (Aldrich Chemical Co. Catalog Handbook of Fine Chemicals 1979-1980, Milwaukee, Wisconsin, p. 133; Pedersen, J. C. JACS 92:386 (1970)) in tetrahydrofuran (prepared from 800 mg potassium hydride and 1.0 g 18-crown-6 ether in 8.7 ml of dry tetrahydrofuran). After stirring for one hour at 0° C. under argon, the mixture is added to 30 ml of water, extracted with 90 mg of diethyl ether and the ethereal extract is washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on 9 g of silica gel eluting with ethyl acetate and hexane. Formula XXIV product (40 mg) is thereby obtained. Silica gel TLC R_(f) is 0.30 in ethyl acetate and hexane (1:1).

EXAMPLE 3 7-Oxo-3α-tetrahydropyran-2-yloxy-2β-[(3'S)-3'-tetrahydropyran-2-yloxy-trans-1'-octenyl]bicyclo[3.3.0]octane (Formula XXV: R₁₈, Y₁, M₆, n, L₁, R₇ are as defined in Example 1).

Refer to Chart A.

A suspension of 0.10 g of the title product of Example 1, 10 μl of 97% formic acid, 0.05 ml of triethylamine, and 0.01 g of 5% palladium on carbon in 2 ml toluene is heated under a nitrogen atmosphere for 30 minutes at 80°-90°. The suspension is cooled, diluted with ethyl acetate, and filtered through diatomaceous earth. The filtrate is washed with 20 ml saturated aqueous sodium bicarbonate (bicarb) and 20 ml brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.13 g of crude product as a yellow oil. Chromatographing on 10 g of silica gel eluting with 25% ethyl acetatein hexane yields 0.10 g of pure title product. Silica gel TLC R_(f) is 0.38 in hexane and ethyl acetate (6:4). NMR absorptions are observed at 5.33-5.78 (multiplet)δ. Infrared absorptions are observed at 1730, 1200, 1160, 1130, 1075, 1035, 1020, and 975 cm⁻¹.

Following the procedure of Example 3, but employing each of the various compounds described in or following Examples 1 and 2, there are prepared each of the various formula XXV products.

By procedures known in the art, each of the various formula XXV products is transformed to known analogs of carbacyclin. For methods to achieve this transformation see British published specifications Nos. 2,014,143 and 2,013,661.

EXAMPLE 4 5-carboxypentanol, t-butyldimethylsilyl ether

A solution of 4 g of sodium hydroxide in 100 ml of methanol and water (4:1) is treated with 10 ml of caprolactone and stirred at ambient temperature under a nitrogen atmosphere. After 20 hours, solvent is evaporated by addition of toluene, yielding 15 g of solid, crude 5-carboxypentanol.

The above solid is suspended in 300 ml of dimethylformamide under a nitrogen atmosphere, cooled to 0° C., treated with 35 g of imidizole, stirred for 15 minutes at 0° C. and 15 minutes at ambient temperature, cooled to 0° C. and treated with 39 g of t-butyldimethyl silylchloride. The resulting solution is then allowed to warm to ambient temperature under a nitrogen atmosphere. After 26 hours, the resulting solution is treated with 8 g of sodium hydroxide in 40 ml of water and 40 ml of methanol, with stirring maintained under a nitrogen atmosphere. After 13 hours, the suspension is acidified to pH 4 with 500 ml of 1 N aqueous hydrogen chloride, then saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate extracts are then washed with 1 N aqueous sodium hydroxide. The basic extracts are then acidified to pH 4 with concentrated hydrochloric acid, saturated with brine, and extracted with ethyl acetate. The ethyl acetate extracts are then washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 22.6 g of a yellow liquid, 5-carboxypentanol, t-butyldimethylsilyl ether. Chromatography on 800 g of silica gel eluting with ethyl acetate and hexane (1:9 to 1:1) yields 14.8 g of 5-carboxypentanol, t-butyldimethylsilylether. NMR absorptions are observed at 0.05 (singlet) and 0.90 (singlet) δ. Infrared absorptions are observed at 3000 (broad) and 1700 cm⁻¹.

Following the procedure of Example 4, but employing each of the various lactones corresponding to the ω-carboxyalkanol compounds of formula XXXII there are prepared each of the various formula XXXII products.

EXAMPLE 5 2-Decarboxy-2(t-butyldimethylsilyloxy)methyl-5-carboxy-6-hydroxy-6α,9-didehydro-CBAhd 1, 11,15-bis(tetrahydropyran)ether (Formula XXXIII): R₂₈ is t-butyldimethylsilyl, Z₁ is --(CH₂)₂ --, n is 1, and R₁₈, M₆, L₁, and R₇ are as defined in Example 1).

Refer to Chart B.

A solution of 0.58 ml of dry diisopropylamine and 20 ml of dry tetrahydrofuran at 0° C. under an argon atmosphere is treated with 2.6 ml of 1.56 M n-butyl lithium in hexane, stirred for 5 to 10 minutes at 0° C., treated with 0.50 g of the title product of Example 4 in 5 ml of tetrahydrofuran, stirred for 15 minutes at 0° C. and 1 hour at ambient temperature, cooled to 0° C., treated with 0.88 g of the title product of Example 1 in 5 ml of tetrahydrofuran, and allowed to slowly warm to ambient temperature under an argon atmosphere. Thereafter, 130 ml of water and 20 ml of brine are added and the mixture extracted with diethyl ether. The ethereal extracts are then washed with 4 ml of 1 N aqueous hydrochloric acid and 150 ml of brine and dried over sodium sulfate, and concentrated under reduced pressure to yield 1.37 g of product. NMR absorptions are 0.05 (singlet), 0.9 (singlet), and 5.1-5.9 (multiplet)δ. IR absorptions are observed at 3300 and 1730 cm⁻¹.

Following the procedure of Example 5, but employing each of the various formula XXXI compounds described following Example 1, there are prepared each of the various formula XXXIII compounds wherein R₂₈ is t-butyldimethylsilyl and Z₁ is --(CH₂)₂ --.

EXAMPLE 6 2-Decarboxy-2-(t-butyldimethylsilyloxy)methyl-6a,9-didehydro-CBA₂,11,15-bis-(tetrahydopyranylether) (Formula XXXIV: R₂₈, Z₁, n, R₁₈, Y₁, M₆, L₁ and R₇ are as defined our Examples 1 and 5).

The reaction product of Example 5 (1.37 g) and 16 ml of methylene chloride is treated with 2.9 ml of dimethylformamide dineopentyl acetal, stirred for 3 hours at ambient temperature under nitrogen, added to 160 ml of ice water and 40 ml of brine, and extracted with diethyl ether. The ethereal extracts are then washed with 150 ml of sodium bicarbonate and 150 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 1.17 g of a brown oil. Chromatography on 100 g of silica gel eluting with 10% ethyl acetate in hexane yields 0.75 g of title product. NMR absorptions are observed at 0.05 (singlet) and 0.9 (singlet)δ. IR absorption is observed at 1250 cm⁻¹. Silica gel TLC R_(f) is 0.26 in 10% ethyl acetate in hexane.

Following the procedure of Example 6, but employing each of the various formula XXXIII compounds described following Example 5, there are prepared each of the various corresponding formula XXXIV products wherein R₂₈ is t-butyldimethylsilyl and Z₁ is --(CH₂)₂ --.

EXAMPLE 7 2-Decarboxy-2-hydroxymethyl-6a,9-didehydro-CBA₂, 11,15-bis(tetrahydropyranyl)ether (Formula XXXV: Z₁, n, R₁₈, Y₁, M₆, L₁, R₇ are as defined in Examples 1 and 5).

Refer to Chart B.

A solution of 0.71 g of the title product of Example 6 and 16 ml of dry tetrahydrofuran in 0° C. under a nitrogen atmosphere is treated with 3.2 ml of 0.75 molar tetra-n-butylammoniumfluoride and tetrahydrofuran. After allowing the reaction mixture to slowly warm to ambient temperature overnight with stirring, 150 ml of brine is added and the resulting mixture extracted with ethyl acetate. The ethyl acetate extracts are then washed with 0.5 normal aqueous potassium bisulfate, 100 ml of sodium bicarbonate, and 100 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield crude title product as a brown oil. Filtering through 25 g of silica gel with 200 ml of ethyl acetate and hexane yields 0.61 g of crude product as a colorless oil. Chromatography on silica gel eluting with 35% ethyl acetate in hexane yields 300 mg of pure title product. NMR absorptions are observed at 5.3-5.8 (multiplet) and 6.0 (broad singlet)δ. Infrared absorptions are observed at 3440 and 1670 cm⁻¹. Silica gel TLC R_(f) is 0.23 in 35% ethyl acetate in hexane.

Following the procedure of Example 7, but employing each of the various formula XXXIV compounds described in the following Example 6, there are prepared each f the various formula XXXV compounds wherein Z₁ is --(CH₂)₂ --.

Following the procedure of Examples 5, 6, and 7, and employing the various starting materials described in and following these examples and each of the various formula XXXII compounds described in the following Example 4, there are prepared each of the various formula XXXV compounds.

EXAMPLE 8 2-Decarboxy-2-hydroxymethyl-6a,9-didehydro-CBA₂ (Formula XXXVI: X₁ is --CH₂ OH, Z₁ is --(CH₂)₂ --, R₈ is hydroxy, Y₁ is trans-CH═CH--, M₁ is α--OH:β--H, L₁ is α-H:β-H and R₇ is n-butyl).

Refer to Chart B.

The title product of Example 7 (0.25 g) is combined with 9 ml of acetic acid, water and tetrahydrofuran (6:3:1) and heated to 37°-40° C. for two hours. Thereafter the resulting mixture is cooled and extracted with diethyl ether. The ethereal extracts are then washed with brine, dried over sodium sulfate and concentrated to yield crude title product. Chromatography on silica gel yields pure title product.

Following the procedure of Example 7, but employing each of the various formula XXXV primary alcohols described in and following Example 7 there are prepared each of the various corresponding formula XXXVI products wherein X₁ is --CH₂ OH. ##STR1## 

I claim:
 1. A carbacyclin analog of formula VIIwherein n is the integer 1 or 2; wherein Y₁ is trans--CH═CH--, cis--CH═CH--, --CH₂ CH₂ --, or --C.tbd.C--; wherein L₁ is α-R₃ :β-R₄, α-R₄ :β-R₃, or a mixture of α-R₃ :β-R₄ and α-R₄ :β-R₃, wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro; wherein Z₁ is (1) --(CH₂)_(g) --C(R₂)₂, wherein g is 0, 1, 2, or 3 and R₂ is hydrogen or fluoro, or (2) trans-CH═CH--;wherein R₇ is (1) --(CH₂)_(m) --CH₃, wherein m is an integer from one to 5, inclusive; (2) phenoxy; (3) phenoxy substituted by one, two or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl; (4) phenyl; (5) phenyl substituted by one, two or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl; (6) benzyl, phenylethyl, or phenylpropyl; or (7) benzyl, phenylethyl, or phenylpropyl substituted by one, two or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl; (8) cis--CH═CH--CH₂ --CH₃ ; or (9) --(CH₂)₂ --CH(OH)--CH₃ ;with the proviso that R₇ is phenoxy or substituted phenoxy, only when R₃ and R₄ are hydrogen or methyl, being the same or different; wherein R₈ is hydroxy, hydroxymethyl, or hydrogen; wherein M₁ is α-OH:β-R₅ or α-R₅ :β-OH, wherein R₅ is hydrogen or methyl; and wherein X₁ is (1) --COOR₁, wherein R₁ is(a) hydrogen; (b) alkyl of one to 12 carbon atoms, inclusive; (c) cycloalkyl of 3 to 10 carbon atoms, inclusive; (d) aralkyl of 7 to 12 carbon atoms, inclusive; (e) phenyl; (f) phenyl substituted with one, 2 or 3 chloro or alkyl of one to 3 carbon atoms; (g) phenyl substituted in the para position by(i) --NH--CO--R₂₅, (ii) --CO--R₂₆, (iii) --O--CO--R₂₇, or (iv) --CH═N--NH--CO--NH₂ wherein R₂₅ is methyl, phenyl, acetamidophenyl, benzamidophenyl, or --NH₂ ; R₂₆ is methyl, phenyl, --NH₂, or methoxy; and R₂₇ is phenyl or acetamidophenyl; inclusive, or (h) a pharmacologically acceptable cation; (2) --CH₂ OH; (3) --COL₄, wherein L₄ is(a) amino of the formula --NR₂₁ R₂₂, wherein R₂₁ and R₂₂ are(i) hydrogen; (ii) alkyl of one to 12 carbon atoms, inclusive; (iii) cycloalkyl of 3 to 10 carbon atoms, inclusive; (iv) aralkyl of 7 to 12 carbon atoms, inclusive; (v) phenyl; (vi) phenyl substituted with one, 2 or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro; (vii) carboxyalkyl of 2 to 5 carbon atoms, inclusive; (viii) carbamoylalkyl of 2 to 5 carbon atoms, inclusive; (ix) cyanoalkyl of 2 to 5 carbon atoms, inclusive; (x) acetylalkyl of 3 to 6 carbon atoms, inclusive; (xi) benzoylalkyl substituted by one, 2 or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, alkoxy of one to 3 carbon atoms, inclusive, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro; (xiii) pyridyl; (xiv) pyridyl substituted by one, 2 or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive; (xv) pyridylalkyl of 6 to 9 carbon atoms, inclusive; (xvi) pyridylalkyl substituted by one, 2 or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy or alkyl of one to 3 carboxy atoms, inclusive; (xvii) hydroxyalkyl of one to 4 carbon atoms, inclusive; (xviii) dihydroxyalkyl of one to 4 carbon atoms, or (xix) trihydroxyalkyl of one to 4 carbon atoms; with the further proviso that not more than one of R₂₁ and R₂₂ is other than hydrogen or alkyl; (b) cycloamino selected from the group consisting of(i) pyrrolidino, (ii) piperidino, (iii) morpholino, (iv) piperazine, (v) hexamethyleneimino, (vi) pyrrolino, (vii) 3,4-didehydropiperidinyl, or (viii) pyrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino, or 3,4-didehydropiperidinyl substituted by one or 2 alkyl of one to 12 carbon atoms, inclusive; (c) carbonylamino of the formula --NR₂₃ COR₂₁, wherein R₂₃ is hydrogen or alkyl of one to 4 carbon atoms and R₂₁ is other than hydrogen, but otherwise as defined above; (d) sulfonylamino of the formula --NR₂₃ SO₂ R₂₁, wherein R₂₁ and R₂₃ are as defined in (c); and (4) --CH₂ NL₂ L₃, wherein L₂ and L₃ are hydrogen or alkyl of one to 4 carbon atoms, inclusive, being the same or different, or the pharmacologically acceptable acid addition salts thereof when
 2. 6a,9-Didehydro-CBA², a carbacyclin analog according to claim
 1. 